KRAS mutations in non-small-cell lung cancer and colorectal cancer: Implications for EGFR-targeted therapies

M. K H Maus, P. P. Grimminger, Philip Mack, S. H. Astrow, C. Stephens, G. Zeger, J. Hsiang, J. Brabender, M. Friedrich, H. Alakus, A. H. Hölscher, Primo N Lara, K. D. Danenberg, H. J. Lenz, David R Gandara

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Background: KRAS mutations are associated with diverse biologic functions as well as prognostic and predictive impact in non-small cell-lung cancer (NSCLC) and colorectal cancer (CRC). In CRC, benefit from monoclonal antibody therapies targeting EGFR is generally limited to patients whose tumors have wild-type (WT) KRAS, whereas data suggest that this association is not present for NSCLC. We hypothesized that the unique tobacco-related carcinogenesis of NSCLC results in a divergence of KRAS MT genotype compared with CRC, contributing to differences in outcomes from EGFR-targeted therapies. Material and methods: Tumor from 2603 patients (838 CRC and 1765 NSCLC) was analyzed for KRAS mutations. DNA was extracted from microdissected formalin-fixed-paraffin-embedded specimens (FFPE) and 7 different base substitutions in codons 12 and 13 of KRAS were determined. Results: KRAS mutation genotype differed significantly between NSCLC and CRC in frequency (25% vs. 39%; p<. 0.001), smoking-associated G>T transversions (73% versus 27%; p<. 0.001), and ratio of transversions to transitions (3.5 vs. 0.79; p<. 0.001). In NSCLC GLY12Cys mutations, resulting from a codon 12 GGT>TGT substitution, were observed in 44% compared to 10% for CRC. In contrast, codon 12 or 13 GLY>ASP substitutions (resulting in a G>A transition) were more frequent in CRC (42%) compared with NSCLC (21%). Conclusion: In this large dataset, KRAS mutation patterns are quantitatively and qualitatively distinct between NSCLC and CRC, reflecting in part differences in tobacco-related carcinogenesis. In light of differences in predictive value for EGFR-directed monoclonal antibody therapy and prognosis for specific KRAS mutations between NSCLC and CRC, these data provide an underlying biologic rationale.

Original languageEnglish (US)
Pages (from-to)163-167
Number of pages5
JournalLung Cancer
Volume83
Issue number2
DOIs
StatePublished - Feb 2014

Keywords

  • Colorectal cancer (CRC)
  • EGFR-targeted therapy
  • KRAS mutations
  • Molecular genetics
  • Non-small-cell lung cancer (NSCLC)
  • Personalized medicine
  • Predictive biomarkers

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

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